Levamisole-resitant mutants of the nematode Caenorhabditis elegans appear to lack pharmacological acetylcholine receptors

doi:10.1016/0306-4522(80)90180-3

Neuroscience

Volume 5, Issue 6, June 1980, Pages 967-989

https://doi.org/10.1016/0306-4522(80)90180-3 Get rights and content

Abstract

The body muscles of the nematode Caenorhabditis elegans contract when the animal is cut in solutions of cholinergic agonists. The pharmacological specificity of the apparent nematode cholinergic receptor is most like a vertebrate nicotink ganglionic receptor. The anthelmintic levamisole resembles nicotine in its effects and acts directly or indirectly as both a cholinergic agonist and antagonist. Mutants at 7 loci conferring extreme resistance to levamisole respond very poorly to cholinergic agonists effective on the wild type. These mutants all share the same uncoordinated motor behavior and contract like the wild type in response to the noncholinergic muscle agonist ouabain. The uncoordinated motor behavior of the mutants and the resistance to levamisole and cholinergic agonists can be copied by exposing the wild type to the cholinergic blocking agent mecamylamine. Another class of mutants (8 loci, 5 corresponding to loci also producing extremely resistant alleles) possesses intermediate resistance to levamisole and cholinergic agonists and behaves pharmacologically and genetically like mutants moderately impaired in the levamisole-sensitive function. A third class of mutants (2 loci) with spasmodic muscle twitching is partially resistant to cholinergic agonists and to ouabain and probably represents defects in the muscle-contraction cycle physiologically downstream from the levamisole-sensitive function. Meta-phenyl-substituted derivatives of levamisole retain considerable biological activity and may be useful in the molecular analysis of our mutants. α-bungarotoxin, benzyltrimethyl-ammonium, and 3-quinuclidinyl benzilate, potential probes of cholinergic receptor function, do not show significant activity in our cut worm assay.

The nature of the observed cholinergic response and the neuronanatomy of C. elegans suggest that the primary response occurs at muscle synapses. We believe that the physiological defect the extremely resistant mutants share is a severe lack of functional muscle acetylcholine receptors and that most of the wild type function of this molecule is not essential to the life of C. elegans. The ability to obtain such mutants may result from there being more than one pharmacological type of nematode cholinergic muscle receptor and/or from the coexistence of a noncholinergic motor mechanism. More generally, the ease with which levamisole-resistant mutants can be isolated (up to 74 mutants in one gene) makes these mutants a favorable system for understanding how a small group of related genes function in a simple animal.

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Citation Excerpt :
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Levamisole-resitant mutants of the nematode Caenorhabditis elegans appear to lack pharmacological acetylcholine receptors

Abstract

J. biol. Chem.

Analyt. Biochem.

Biochem. Pharmac.

J. molec. Biol.

Brain Res.

Biochim. biophys. Acta

Neuroscience

Tetrahedron Lett.

Devl Biol.

Biochim. biophys. Acta

Biochem. Pharmac.

The mechanism of the paralysing action of tetramisole on Ascaris muscle

Br. J. Pharmac.

Amantadine: neuromuscular blockade by suppression of ionic conductance of the acetylcholine receptor

Science, N.Y.

Aspects of the pharmacology of a new anthelmintic: pyrantel

Br. J. Pharmac.

The role of a reactive disulphide bond in the function of the acetylcholine receptor at the frog neuromuscular junction

J. Physiol., Lond.

The genetics of Caenorhabditis elegans

Genetics, Princeton

Resolution and racemization of dl-tetramisole, dl-6-phenyl-2,3,5,6-tetrahydroimidazo [2,1-b]thiazole

J. med. Chem.

The effect of ouabain on the efflux of sodium from a giant squid axon

J. Physiol., Lond.

The cholinergic receptor protein in its membrane environment

A. Rev. Pharmac.

The mode of action of four anthelmintics

Experientia

The Mathematics of Diffusion

Electrophysiology of the somatic muscle celis of Ascaris lumbricoides

J. cell. comp. Physiol.

The physiological role of acetylcholine in the neuromuscular system of Ascaris lumbricoides

Archs Int. Physiol.

Mechanism of the paralysing action of piperazine on Ascaris muscle

Br. J. Pharmac.

Inhibitory action of y-aminobutyric acid (GABA) on Ascaris muscle

Experientia

The electrical and mechanical activity of the esophageal cell of Ascaris lumbricoides

J. gen. Physiol.

Origin and blockade of the synaptic responses of curarized sympathetic ganglia

J. Physiol., Lond.

Some pharmacodynamic effects of the nematocides: methyridine, tetramisole and pyrantel

J. Pharm. Pharmac.